PROJECT SUMMARY/ABSTRACT The process of aging causes functional decline of the hematopoietic system, including reduced capacity for regeneration, increased risk of infections, and increased risk of certain forms of blood cancer. This is a significant health concern due to the worldwide increase in the age of the population and incidence of these age-related conditions. No intervention therapies currently exist to prevent functional decline of the hematopoietic system with aging, largely due to a lack of understanding of the cellular and molecular alterations that occur at the age of onset to cause functional hematopoietic decline. As hematopoietic stem cells assure long-term tissue maintenance, it is widely accepted based on experimental evidence that loss of proper hematopoietic stem cell function in the bone marrow during aging is a major cause of hematopoietic decline. Our preliminary data demonstrate that at the age of onset of functional hematopoietic decline, alterations in the bone marrow microenvironment are necessary and sufficient to cause hematopoietic stem cell aging, and identify reduced levels of the signaling molecule Insulin-like Growth Factor 1 (IGF-1) in the bone marrow as a candidate driver of hematopoietic stem cell aging. This project will use cellular and molecular biological approaches in aging mice to characterize the specific cellular and molecular alterations in the aging bone marrow microenvironment and how these cause functional decline of hematopoietic stem cells, including the specific cell type(s) responsible for reduced production of IGF-1 and how reduced IGF-1-mediated signaling drives functional decline of hematopoietic stem cells. Results of this project will reveal the mechanisms causing functional decline of the hematopoietic system with aging, and identify targeted, molecular- and cell type-specific therapeutic strategies to preserve regenerative capacity and immune cell function during aging.